Experimental autoimmune encephalomyelitis (EAE) is a central nervous system (CMS) autoimmune disease that resembles the clinical and pathological features of human multiple sclerosis (MS). In both cases, there are clearly regulatory mechanisms as an individual can be susceptible or resistant to the disease. In addition, individuals recovering from the initial attack may fall victim to subsequent spontaneous cycles of remission/relapses relapses. This laboratory's long-term goals are to understand the mechanisms underlying EAE resistance and development remitting/relapsing disease. Recently, regulatory T cells (Treg) have been shown to inhibit the activation of immune effector cells. Of particular relevance is the finding that depleting natural Treg cells (nTreg) renders mice susceptible to EAE induction. We find that this loss of resistance occurs in one strain of mice (SJL.B) but not in another (B6). Specific aim 1 will investigate if this Treg mechanism is universally utilized by EAE resistant mouse strains to maintain resistance of disease induction. A hypothesis to account for the insensitivity of B6 mice to anti-CD25 treatment is also proposed. Specific aim 2 explores the possibility that antigen-induced Treg cells (Treg) may have differential characteristics from nTreg cells. By using Thy-1 congenic mouse strains developed in this laboratory, the trafficking patterns of Treg cells from the lymphoid tissues to the CNS will be tracked. Of particular interest is the tissue locations whereby Treg cells most efficiently inhibit encephalitogenic effector cells to prevent disease. A possible link between Treg cells and remitting/relapsing EAE is made in specific aim 3. Here, the mechanisms of remitting/relapsing EAE will be investigated from the prospects of epitope spreading, Treg cells and the roles of the acute disease-initiating T cells, using Thy-1 congenic mice. In summary, this project will provide a better understanding of how regulatory T cells help to resist development of EAE and MS. The project also studies the mechanisms of how disease relapses occurs, with the ultimate aim of designing better therapeutic approaches toward management of this autoimmune disease.